N-Heterocyclic carbene-catalyzed [4 + 1] annulation of phthalaldehyde and imines

Article abstract of DOI:10.1039/c1ob05092c

The diastereoselective synthesis of cis-2-amino-3-hydroxyindanones was realized by the N-heterocyclic carbene-catalyzed [4 + 1] annulation of phthalaldehyde and imines, which may involve a tandem aza-benzoin reaction and aldol reaction.

Full text of DOI:10.1039/c1ob05092c

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N-Heterocyclic carbene-catalyzed [4 + 1] annulation of phthalaldehyde and
imines†
Fang-gang Sun and Song Ye*
Received 18th January 2011, Accepted 23rd March 2011
DOI: 10.1039/c1ob05092c
The diastereoselective synthesis of cis-2-amino-3-hydroxy-
indanones was realized by the N-heterocyclic carbene-
catalyzed [4 + 1] annulation of phthalaldehyde and imines,
which may involve a tandem aza-benzoin reaction and aldol
reaction.
During recent decades, N-heterocyclic carbenes (NHCs) have
been found to be efficient catalysts for a wide variety of
reactions.1 Following the pioneering NHC-catalyzed benzoin
condensation of aldehydes,2 the aza-benzoin reaction of alde-
hydes with imines and the Stetter reaction of aldehydes with
Michael acceptors have also been developed.3 In the past few
years, NHCs were further demonstrated very successfully as
catalysts for the extended umpolung of functionalized aldehydes,
such as a,b-unsaturated-, a-halo-, a, b-epoxy-, a, b-aziridinyl-,
Scheme 1 NHC-catalyzed annulation reaction of phthalaldehyde.
and b-lactam aldehydes.4 Furthermore, NHC catalysts were
also effective for transesterification,5 polymerization of lactides,6
acylation,7 umpolung of Michael acceptors,8 aza-Morita–Baylis–
Hillman reaction,9 activation of silylated nucleophiles,10 reactions
of ketenes11,12 and other reactions.13
Tandem reactions, which allow rapid construction of complex
Scheme 2 NHC-catalyzed tandem aza-bezoin–Michael reaction with
imines by You et al.
molecules from simple starting materials in one pot, have proved
useful in modern synthesis.14 Very recently, Gravel et al. reported
an efficient synthesis of indanes by NHC-catalyzed tandem reac-
tion of aldehydes with Michael acceptors.15 We reported a tandem
Stetter–aldol reaction of phthalaldehyde to give hydroxytetralones
as the [4 + 2] annulation product or hydroxyindanones as the
[4 + 1] annulation product by employing monoactivated or 1,2-
diactivated Michael acceptors (Scheme 1, reactions a and b).16
In this paper, we wish to report an NHC-catalyzed tandem
reaction of phthalaldehydes with imines, which give 2-amino-3-
The optimization of the reaction conditions for
the model reaction of phthalaldehyde and tert-butyl
phenyl(phenylsulfonyl)methylcarbamate (2a) was summarized
in Table 1. Initially, potassium phosphate was used as the
base both for the generation of NHC from a thiazolium salt
and for generation of imine from its precursor. The reaction
catalyzed by thiazolium salt 4a in THF gave the corresponding
[4 + 1] annulation product in 55% yield with exclusive cis-
diastereoselectivity (entry 1). No improvement was observed for
the reaction in toluene, dichloromethane or acetonitrile (entries
2–4). The yield was improved to 70% when Cs2CO3 (0.2 equiv.) was
used to generate the carbene, and K2CO3 (2.0 equiv.) to facilitate
the formation of the imine (entry 5). Further improvement was
achieved when diisopropylethylamine (2.0 equiv.) was used (entry
6). Thiazolium iodide 4b with an N-ethyl substituent worked
albeit with a decreased yield (entry 7). Thiazolium chloride 4c,
without the free hydroxy group, also worked well for the reaction
(entry 8).
17
hydroxyindanone as the [4 + 1] annulation product instead of
the expected [4 + 2] annulation product (Scheme 1, reaction c).
During the preparation of this manuscript, You et al. reported
a novel NHC-catalyzed tandem aza-benzoin–Michael reaction of
aldehydes and imines (Scheme 2).18
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory
of Molecular Recognition and Function, Institute of Chemistry, Chinese
Academy of Sciences, Beijing, 100190, China. E-mail: songye@iccas.ac.cn
† Electronic supplementary information (ESI) available: Copies of 1H
NMR, 13C NMR and CD spectra. CCDC reference number 807044. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c1ob05092c
The structure of indanone 3a was unambiguous established by
X-ray analysis of its crystal (Fig. 1).†19
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Table 1 Optimization of reaction conditions
Entry
4a–c
Base (2.0 equiv.)
Solvent
Yield (%)c
1b
2b
3b
4b
5
6
7
8
4a
4a
4a
4a
4a
4a
4b
4c
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
DIPEA
DIPEA
DIPEA
THF
55
37
34
28
70
76
59
68
toluene
CH2Cl2
CH3CN
THF
THF
THF
THF
Scheme 3 Synthesis of isoquinolinone 6.
a NHCs 4a¢–4c¢ were generated from their precursors 4a–4c (20 mol%) and
Cs2CO3 (20 mol%) at room temperature for 20 min, and used immediately
for the entries 5–8. b No Cs2CO3 was added for entries 1 to 4. c Isolated yield
of pure cis-isomer, and no trans-isomer was observed for all the entries.
Fig. 1 X-Ray structure of indanone 3a.
With the optimized reaction conditions in hand, the scope of
the arylimines was then briefly investigated (Table 2). An imine
with a p-chlorophenyl group gave the corresponding indanone
in 83% yield (entry 2). Imines with electron-donating groups (4-
Me, 4-MeO) on the phenyl ring worked but resulted in decreased
yields (entries 3 and 4). The imine 2e with a m-chlorophenyl group
showed similar reactivity compared with p-chlorophenylimine,
affording the corresponding indanone 3e in 87% yield (entry 5).
m-Nitrophenylimine worked very well for the [4 + 1] annulation
reaction (entry 6). Heteroarylimines, such as 2-pyridylimine and
2-thienylimine, also worked well, giving the annulation product
in very good yields (entries 7 and 8). N-Benzyl carbamate or N-
benzoylimine is also compatible with the reaction (entries 9 and
10). It should be noted that only cis-isomers are observed for all
reactions in Table 2.
The resulting highly functionalized indanones afford oppor-
tunity for chemical transformations. Interestingly, when the in-
danone 3j was subject to the condition of DEAD and PPh3, the
generation of the expected dihydrooxazole 5 was not observed.20
However, the isoquinolinone 6 was isolated in good yield, which
may involve the aziridine 8 as the key intermediate (Scheme 3).21
The structure of isoquinolinone 6 was proved by the synthesis of
debenzoyl product 7 by a known procedure.22
Scheme 4 Possible catalytic cycle.
gives Breslow intermediate A, which reacts with imine afford-
ing aza-benzoin reaction intermediate B. Proton shift(s) gives
intermediate C, which is fragmented to regenerate the catalyst
and a-aminoketone 9.23 The intramolecular aldol reaction of 9
affords the final 2-amino-3-hydroxyindanone 3. An alternative
reaction pathway without involving a-aminoketone 9 is also
possible (Scheme 5). Proton shift of intermediate B gives a
carbanion D, which attacks the aldehyde intramolecularly to give
the cycloadduct E. Fragmentation of cycloadduct E releases the
NHC catalyst and affords the final 2-amino-3-hydroxyindanone
3.
In conclusion, an N-heterocyclic carbene-catalyzed tandem
aza-benzoin and aldol reaction of phthalaldehyde and imines
was developed, which affords the corresponding cis-2-amino-
3-hydroxyindanone as the formal [4 + 1] annulation product
with exclusive cis-diastereoselectivity. The interesting reaction
A possible catalytic cycle of the NHC-catalyzed reaction is
depicted in Scheme 4. The addition of the NHC to phthalaldehyde
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Table 2 NHC-catalyzed [4 + 1] annulation of phthalaldehyde and imines
Entry
1
2
3
Yielda (%)
76
2
3
4
5
83
56
40
87
6
91
7
8
87
93
9
66
53
10
a Isolated yield of pure cis-isomer.
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The Royal Society of Chemistry 2011
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